World of Drug Information
World of Drug Information - Volume 10, Issue 2 - June 1999

In This Issue ...
 Current Clinical Issues 
 Electronic Pediatrics 
 Search Tips 
 Perspective From an IDIS Subscriber 
 Year 2000 Compliance 
 Key References 
 FDA Approvals 
 New Valid Drug Term 
 Information Explosion 
 1999 Exhibit Schedule 
 Staff Profile 
CURRENT CLINICAL ISSUES
The Quest for a Vaccine

Malaria, a potentially life-threatening disease, affects over 300 million people worldwide each year causing approximately three million deaths (WHO-OHS). People of all ages are vulnerable to this predominantly tropical disease, but young children and pregnant women face a higher risk of developing severe complications requiring immediate medical intervention. Malaria is endemic in over 90 countries around the world and remains a major public health burden and a socio-economic problem for some tropical and subtropical countries in sub-Saharan Africa and South-East Asia. These epidemiological data are staggering for a disease that had been effectively eradicated in many parts of the world, partially eliminated but re-emerging in others and now spreading in new geographic areas. This old disease is currently causing one of the highest death tolls of all the communicable diseases.

Infection:

Malaria is a protozoan infection caused by an intracellular parasite of the genus Plasmodium and transmitted from person to person mostly through the bite of an infected female Anopheles mosquito. Of the hundred species of the Plasmodium genus only four can transmit malaria to a human host - P. falciparum, P. vivax, P. ovale and P. malariae (White, 1998). The various forms of malaria differ in their epidemiologic distribution, geographic variation, prognosis and treatment. Plasmodium falciparum, the most predominant parasite causing malaria in Africa, South East Asia and Latin America has the highest mortality rate due to its complications and drug resistance. Plasmodium ovale malaria is the least prevalent. Plasmodium parasites are vector specific - i.e. hundreds of Anopheles mosquito species exist but only approximately fifty of them can be a "flying syringe" and inject the parasite by way of their saliva into the host.

Cycle

The malaria parasite has a complex life cycle, shared between an intermediate host, a human or higher primate, and a vector, an Anopheles mosquito (Malaria Foundation). The plasmodial forms found in the salivary glands of an infected anopheline mosquito are called sporozoites. A bite from an infected female Anopheles inoculates the sporozoites to the host. The sporozoites follow the blood stream, migrate to the liver and invade the hepatocytes. During this intrahepatic, exo-erythrocytic or pre-erythrocytic stage, the sporozoite evolves into a trophozoite, matures into a fully developed schizont, a multinuclear form of Plasmodium which by asexual reproduction produces the merozoites. The merozoites released from the liver cells reach the blood stream, and bind on the surface of the erythrocytes. Within the red blood cells, after maturation and rapid asexual replication cycles, they rupture the red blood cells and release a second generation of merozoites that will invade healthy erythrocytes. This asexual erythrocytic reproduction stage is short, lasting only two to three days and corresponds to the symptomatic stage of malaria. In the blood, after a variable number of cycles of asexual division, some plasmodial merozoites differentiate into mature male and female gametocytes (White, 1998). When a female anopheline mosquito bites an infected person, blood containing both gametocytes is transferred into the mosquito gut where by fusion and division the gametocytes are transformed into infective sporozoites. These motile sporozoites migrate later to the mosquitoís salivary glands and are released into the saliva during a blood meal, infecting another person and perpetuating the parasite life cycle.

Presentation

The incubation period is usually from one week to 10 days, but sometimes the first symptoms do not occur until months or even a year or two after the sting of an infective female anopheline mosquito. Malaria presentation is non-specific (White, 1998). Fever, periodic chills, sweating, shivering, myalgia, headaches, vomiting and nausea can lead to a misdiagnosis. Although several methods of malaria detection are available, definite malaria diagnosis must be confirmed by the presence of the plasmodium parasites in the Giemsa-stained peripheral blood smear of a febrile patient. The prognosis is usually quite favorable if malaria is diagnosed and treated early in the course of the disease. Dangerous and fatal complications of falciparum malaria such as black water fever, cerebral malaria, algid malaria and anemia can occur particularly in young children and pregnant women.

Search for a vaccine

The search for a treatment of "Mal Aria," a disease thought to be caused by "bad air from the swamps" and manifested by "repetitive fever episodes" is not new. The use of Artemisia infusions in China and the bark of Cinchona in South America were known to be effective centuries ago but malaria is still an unsolved global health problem.

Could a vaccine be the answer for a disease that kills 200-300 persons every hour or one person every 12 seconds worldwide, a disease with increasing drug resistance, and only partially effective vector eradication programs? The challenge is to design a single vaccine that can provide long term immunity against specific Plasmodium species having complex genetic diversity and a multistage life cycle (Kwiatkowski, 1997). The potential malaria vaccine must also be effective in malaria-naive subjects and semi-immune people living in endemic malaria areas.

The identification of the circumsporozoite protein, a major polypeptide coating the plasmodial sporozoite surface, and the cloning and sequencing of its encoding genes have led to a pre-erythrocytic candidate vaccine, the sporozoite vaccine (Nussenzweig, 1989). Synthetic and recombinant DNA Plasmodium falciparum sporozoite vaccines given intramuscularly are found to be safe and provide short-term immunity against plasmodial sporozoites (Ballou, 1987). Several techniques have been tried to achieve higher immunogenicity such as the use of more potent immunostimulant adjuvants, liposomes encapsulation or attenuated salmonella vector (Rickman, 1991; Gordon, 1995; Gonzalez, 1994; Heppner, 1996). A clinical randomized trial of a hybrid of the sporozoite vaccine conducted in forty-six malaria naive subjects, shows a potential protection against experimental sporozoites challenge (Stoute, 1997). However, the results of its recent follow-up study report the lack of a long-lasting protective immune response at a second experimental challenge six months post initial challenge (Stoute, 1998).

Vaccines targeting the asexual erythrocytic stage of Plasmodium seem to be another logical approach to protect against clinical attacks of malaria (Nussenzweig, 1994). The genes chosen for the asexual blood stage vaccine are those encoding the merozoite surface antigens. SPf66 is a synthetic vaccine derived from a polymerization of three different antigens from the Plasmodium merozoite surface protein (asexual erythrocytic stage) and repeat amino-acid sequences derived from the circumsporozoite protein (preerythrocytic stage). Numerous studies have been published in reference to SPf66 safety, immunogenicity and efficacy. The results of a first large field trial conducted in Columbia involving almost one thousand subjects receiving a SPf66 vaccine series at a dose of three 0.5 ml injected subcutaneously show an increase in SPf66 antibody titer in 93% of the vaccinees and no adverse reactions in 95.7% (Amador, 1992). Phase I clinical studies of a US manufactured SPf66 conducted in a smaller trial in the United States (Gordon, 1996) and in Thailand provide further evidence of SPF66 safety and encouraging immunogenicity (76% seroconversion) (Nosten, 1997). A Phase III randomized, double-blind, placebo-controlled study conducted in Columbia demonstrates its effectiveness in protecting against Plasmodium falciparum malaria clinical episode in 33.6% of the vaccinated population with a higher rate in 1-4 year old children (77%) (Valero, 1993). Subsequently, this so-called "Patarroyoís vaccine" has been extensively tested, undergoing large field trials in Southeast Asia, South America and Africa encompassing a total of more than thirty thousand people world-wide. Results of these studies are divergent ranging from no overall protective effects (Nosten, 1996; DíAlessandro, 1995; Haywood, 1999; Urdaneta, 1998) to 31-55% efficacy rate (Valero, 1993; Noya, 1994; Alonso, 1994). A Cochrane collaboration systematic review of six SPf66 randomized placebo-controlled trials with episode of first attack of malaria as primary outcome report an efficacy of only 23% (95% C.I. 12%-32%) and suggests "cautious optimism" (Alonso, 1994).

Can a multistage, multiantigen, multilayer polyvalent vaccine be an alternative and promote effective immunity (Stanley, 1998)? A trial of NYVAC-Pf7 vaccine, a vaccinia-vectored vaccine containing seven antigens from all stages of Plasmodium falciparum life cycle conducted in 59 volunteers indicates only modest antibody response with no evidence of efficacy against experimental mosquito-bite-induced malaria (Ockenhouse, 1998).

CONCLUSION

Partial immunity elicited by chronic plasmodial exposure, age of the patient, parasiteís complex life cycle, parasiteís prevalence and intensity, multiplicity of the infection, and host immune status are all challenges encountered during the search for an effective malaria vaccine.

Now that complete genetic sequence of Plasmodium falciparum has been identified and cytotoxic T lymphocytes response to plasmid DNA encoding malaria circumsporozoite protein has been evaluated in healthy malaria-naïve volunteers (Wang, 1998), could genetic engineering advances bring new hope for an effective malaria vaccine? The quest for a Malaria Vaccine Öthe quest for a global malaria eradication (Malaria Foundation).

 

IDIS Malaria CITATIONS (As of 5/17/99)
TOPIC # Hits TOPIC # Hits
MALARIA
2156
MALARIA VACCINE
74
P. falciparum
1472
Sporozoite Vaccine
16
P. ovale
42
SPf66 Vaccine
15
P. quartan
48
NYVAC-Pf7
1
P. vivax
293
MALARIA COMPLICATION
Malaria Unspecified 
647
Cerebral Malaria
68
IN SPECIAL POPULATIONS Complication Unspecified
57
Pregnant Women
148
MALARIA RESISTANCE
Children
783
Treatment
114
MALARIA GUIDELINES
16
Drug Resistance
201
 
ThaiBinh TonThat, R.Ph., Pharm.D.

References

1. Alonso PL, Smith T, Armstrong Schellenbe, Masanja H, et al. Randomised trial of efficacy of SPF66 vaccine against plasmodium falciparum malaria in children in southern Tanzania. Lancet, 1994;344:1175-1181. (IDIS article number 338202)

2. Amador R, Moreno A, Murillo LA, Sierra O, et al. Safety and immunogenicity of the synthetic malaria vaccine SPF66 in a large field trial. J Infect Dis, 1992;166:139-144. (IDIS article number 298734)

3. Ballou WR, Hoffman SL, Sherwood JA, Hollingdale MR, et al. Safety and efficacy of a recombinant DNA plasmodium falciparum sporozoite vaccine . Lancet, 1987;1:1277-1281. (IDIS article number 231229)

4. D'alessandro U, Leach A, Drakeley CJ, Bennett S, et al . Efficacy trial of malaria vaccine SPF66 in Gambian infants. Lancet, 1995;346:462-467. (IDIS article number 353147)

5. Gonzalez C, Hone D, Noriega FR, Tacket CO, et al. Salmonella Typhi vaccine strain CVD 908 expressing the circumsporozoite protein of plasmodium falciparum: strain construction and safety and immunogenicity in humans. J Infect Dis, 1994;169:927-931. (IDIS article number 328668)

6. Gordon DM, Duffy PE, Heppner DG, Lyon JA, et al. Phase I safety and immunogenicity testing of clinical lots of the synthetic plasmodium falciparum vaccine SPF66 produced under good manufacturing procedure conditions in the United States. Am J Trop Med Hyg, 1996;55:63-68. (IDIS article number 371661)

7. Gordon DM, McGovern TW, Krzych U, Cohen JC, et al. Safety, immunogenicity, and efficacy of a recombinantly produced plasmodium falciparum circumsporozoite protein-hepatitis b surface antigen subunit vaccine. J Infect Dis, 1995;171:1576-1585. (IDIS article number 348466)

8. Graves P. Human malaria vaccines (Review). In: The Cochrane Database of Systematic Reviews, 4, 1998. Oxford: Update Software.

9. Haywood M, Conway D, Weiss H, et al. The epidemiology of multiple plasmosium faciparum infections: reduction of the mean of number of plasmodium falciparum genotypes in Gambian children immunized with the malaria vaccine SPF66. Trans R Soc Trop Med Hyg, 1999;93:S65-S68. (IDIS Article Number 422543)

10. Heppner DG, Gordon DM, Gross M, Wellde B, et al. Safety, immunogenicity, and efficacy of plasmodium falciparum repeatless circumsporozoite protein vaccine encapsulated in liposomes. J Infect Dis, 1996;174:361-366. (IDIS article number 371184)

11. Kwiatkowski D, Marsh K. Development of a malaria vaccine. Lancet, 1997;350:1696-1701. (IDIS article number 396553)

12. Malaria Foundation International. URL: http://www.malaria.org Available from Internet. Accessed 1999 May 17.

13. Nosten F, Luxemburger C, Kyle DE, Ballou WR, et al. Randomised double-blind placebo-controlled trial of SPF66 malaria vaccine in children in northwestern Thailand. Lancet, 1996;348:701-707. (IDIS article number 373221)

14. Nosten F, Luxemburger C, Kyle DE, Gordon DM, et al. Phase I trial of the SPF66 malaria vaccine in a malaria-experienced population in southeast Asia. Am J Trop Med Hyg, 1997;56:526-532. (IDIS article number 387432)

15. Noya O, Gabaldon Berti Y, Alarcon De Noya B, Borges R, et al. A population-based clinical trial with the SPF66 synthetic plasmodium falciparum malaria vaccine in Venezuela. J INFECT DIS, 1994;170:396-402. (IDIS article number 335900)

16. Nussenzweig RS, Long CA. Malaria Vaccines: Multiple Targets. Science, 1994;265:1381-1383. (IDIS article number 335596)

17. Nussenzweig RS, Nussenzweig V. Antisporozoite vaccine for malaria: experimental basis and current status (suppl). Rev Infect Dis, 1989;11:S579-S585. (IDIS article number 255279)

18. Ockenhouse CF, Sun PF, Lanar DE, Wellde BT, et al. Phase I/IIa safety, immunogenicity, and efficacy trial of NYVAC-PF7, a pox-vectored, multiantigen, multistage vaccine candidate for plasmodium falciparum malaria. J Infect Dis, 1998;177:1664-1673. (IDIS article number 407151)

19. Rickman LS, Gordon DM, Wistar R, Krzych U, et al. Use of adjuvant containing mycobacterial cell-wall skeleton, monophosphoryl lipid a, and squalane in malaria circumsporozoite protein vaccine. Lancet, 1991;337:998-1001. (IDIS article number 280219)

20. Stoute JA, Kester KE, Krzych U, Wellde BT, et al. Long-term efficacy and immune responses following immunization with the RTS, S malaria vaccine. J Infect Dis, 1998;178:1139-1144. (IDIS article number 415237)

21. Stoute JA, Slaoui M, Heppner DG, Momin P, et al. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against plasmodium falciparum malaria. N Engl J Med, 1997;336:86-91. (IDIS article number 377920)

22. Stanley SL. Malaria vaccines: are seven antigens better than one? Lancet, 1998;352:1163-1164. (IDIS Article Number 417794)

23. Urdaneta M, Prata A, Struchiner C J, Tosta C E, et al. Evaluation of SPF66 malaria vaccine efficacy in Brazil. Am J Trop Med Hyg, 1998;58:378-385. (IDIS article number 404100)

24. Valero MV, Amador LR, Galindo C, Figueroa J, et al. Vaccination with SPF66, a chemically synthesised vaccine, against plasmodium falciparum malaria in Colombia. Lancet, 1993;341:705-710. (IDIS article number 311469)

25. Wang R, Doolan DL, Le TP, Hedstrom RC, et al. Induction of antigen-specific cytotoxic T Lymphocytes in humans by a malaria DNA vaccine. Science, 1998;282:476-480. (IDIS article number 412663)

26. White NJ, Breman JG. Malaria and other diseases caused by red blood cell parasites. In: Harrisonís principles of internal medicine. 14th ed. Fauci, Braunwald et al., eds. McGraw-Hill. Health Professions Division 1998:1180-1189.

27. WHO-OHS Home Page. URL: http://www.who.int/ctd/html/malaria.html Available from Internet. Accessed 1999 May 17.



NEW ELECTRONIC VERSION OF PEDIATRICS

IDIS is responding to the trend of electronic journal publishing. Effective May 1999, the IDIS database will include Pediatrics electronic pages, the Internet section of the journal Pediatrics. These monthly original publications available only on the Internet are peer-reviewed and meet the IDIS criteria for article inclusion. An example of an IDIS bibliographic citation:

PEDIATRICS, vol 101, iss E5, p E1, yr 1998
The issue number includes E to denote the electronic issue, and the page is the electronic article number. The 1997 and 1998 back issues of the electronic edition will also be included in the database.

We will continue to include the print version of Pediatrics along with this new electronic version.


SEARCH TIPS

Searching with Drug Classes
Literature searches are often constructed to narrow the focus and avoid unwanted material. However, there are times when taking a broader approach would be of benefit. A couple examples are searches for drug interactions or for general information on managing a disease state, such as heart disease. Many of the articles that provide this type of information do so by including long tables of drugs or by listing categories of drugs. In some cases, these articles are indexed under the drug classes rather than listing each individual drug.

As an example, if you want information about drug interactions with nifedipine, you can conduct a search specifically for nifedipine, but you might also find valuable information by conducting a search with the broader drug class term. Each of the searches should include the topic of interest, in this case INTERACTION, in the title field. For instance, by using INTERACT* in the title field and NIFEDIPINE as the drug term, 116 articles are retrieved. If the drug term "VASODILATORS-CA*" is searched there are 52 hits, and by using "CARDIAC AGENTS" there are 34 hits.

Searches using truncated assigned drug numbers will usually retrieve even more. The assigned drug number for "CARDIAC AGENTS" is 2404000. Truncating this term to 2404* and conducting the search for interactions brings up 781 articles. The drug number for "VASODILATORS-CA CHANNEL BLOCK" is 24120400, and by using 241204* there are 321 articles.

The search can also be conducted by using the IDIS descriptor for drug interactions. The term is 50 DRUG INTERACTION, and the search should include the drug name or assigned number in the drug field and the descriptor number 50 in the descriptor field. This retrieves 422 articles for NIFEDIPINE or 24120416 and 89 articles for "CARDIAC AGENTS" OR 24040000.

There are 585 hits for a drug such as PHENYTOIN, which is involved in many drug interactions. If the drug term ANTICONVUL* is used, then 83 articles are retrieved. Combining the drug terms PHENYTOIN OR ANTICONVUL* retrieves 652 articles.

Many articles on the management of common disease states give valuable information without referring to individual drugs but give classes of drugs instead. The same is true for articles on prescribing patterns and for drug interactions. If you do not find the material you need under a specific drug, try using the more inclusive terms. Using the broader term may not capture more articles than the specific drug term, but it might bring up different, valuable articles that would otherwise be missed.

Nicola Sarrazin, R.Ph., Pharm.D.
 

Perspective from an IDIS Subscriber

Toxic Psychosis vs Toxic Serotonin Syndrome?

TO: Staff Neurologist, Movement Disorder Clinic

RE: Toxic psychosis vs toxic serotonin syndrome?

FAMILY HISTORY: negative for Parkinsonís disease or psychiatric disorders

PAST MEDICAL HISTORY:

[related to Parkinsonís disease diagnosis Ė from patient, wife and the medical record]
- history of R shoulder pain predated Parkinsonís diagnosis by many years;

- episode in 1960ís resulted in the patientís Ďdragging a legí since he was in his 30ís;

- in the 1980ís [Boston] admitted for workups of slurred speech, leg drag MRI Ė no evidence of stroke or multiple sclerosis;

- diagnosis of Parkinsonís made in 1984 the patient was started on Sinemet 25/100 TID
he noticed improvement in his speech, less drooling, improved gait, increased energy and less pain in the R shoulder area;

- for the next 2-3 years he was maintained on Sinemet 25/100 TID, without significant change in his clinical situation;

- around 1987-1988 the AM dose of his Sinemet regiment was increased to 25/250 which gave him a "kick start" to his day,    he continued to use 25/100 for the two other daily doses until 1995;

- selegiline 5 mg BID was added in late 1989 or early 1990, without significant impact Ė recently removed from regimen;

- moved to Florida around 1995, the patient now reports dyskinesia Ė Sinemet dose was reduced to 25/100 TID by Bay Pines VA;

- 1997-1998 the patient is seen in the Movement Disorder Clinic; pergolide was added to his regimen in 1998, he started on 0.25 mg QID with dose increases of 0.25 mg/week until the total daily dose had been increased to 7 mg over approximately seven months [1.75 mg QID];

- on September 1, 1998 the patient is seen at Bay Pines VAMC; the total daily dose of Pergolide was unclear;

- wife related patientís long history of nighttime hallucinations associated with Sinemet which were apparently not frightening and were understood to be toxic. During the period from December 1998 Ė February 1999 she noticed that the patient had more frequent delusional episodes than usual and continued to experience the non-frightening hallucinations which were not reported.

Chief Complaint and History of Present Illness:

On February 11, 1999 the patientís wife called Bay Pines VAMC. The wife states patient is having hallucinations, they are real bad now. The patient describes hallucinations of "substances oozing out of his skin and eyes." This was frightening to both the patient and his wife.

Nature of hallucinations [2/11/99]:

- mental status: the patient was fully oriented and not confused during the hallucination; denied agitation, depression;

- time of day: variable;

- preceded by unformed images: no recollection;

- formed image:[yes] his own body, with substances oozing out of skin, eyes, etc.;

- any non visual hallucinations: possible olfactory features, bad body odor just after taking shower, denied voices or tactile features;

- related to dose increase of medication: [PROBABLY] dates of actual increases in his pergolide regimen are unclear. His total daily prescribed pergolide dose was 7 mg from October 1998 through the middle of January 1999. On 2/2/1999 his prescribed pergolide dose was changed to 7 mg/day alternating with 3.5 mg every other day.

- remitted when dopamine agonist dose reduced: YES, within 48 hours after the pergolide dose was reduced to 4 mg/day, on 2/11/1999, the patient reported substantial resolution of the toxic syndrome.

The patient denies confusion, agitation, headache, dizziness, tachycardia, diaphoresis, tachypnea, nausea, flushing, diarrhea, abdominal cramps, tremor, ataxia, worsened muscle rigidity, myoclonus or ankle clonus during the hallucinations.

Primary Care visit 3/2/99: No more hallucinations, stronger and more flexible; Pergolide dose reduced to 0.75 mg QID, also on Sinemet CR 50/200 in the AM and Sinemet 25/100 at 1300 and 1800.

Literature

Toxic hallucinations Ė dopamine agonists

Levo-dopa, dopamine agonists and the various anticholinergic agents used in the treatment of Parkinsonís disease are among the most common causes of toxic hallucinations associated with the therapeutic use of drugs. However, hallucinations have also been reported in patients on SSRIís, tricyclics, beta blockers, benzodiazepines, and a variety of other drugs. Goetz (1982), Lieberman (1998), and Cummings (1991) have reviewed behavioral complications reported during the drug therapy of Parkinsonís disease. Hallucinations have been described with the use of bromocriptine in the treatment of Parkinsonís disease (Serby, 1978) and with very low doses in the treatment of pituitary tumors (Turner, 1984).

Stern and colleagues (Stern, 1984) studied 19 Parkinsonís patients with inadequate response to levodopa or bromocriptine, or clinical fluctuations with no known history of psychiatric disorders. Six of the 19 patients experienced transient psychiatric symptoms or intellectual changes while on pergolide. The pergolide doses were as follows:

Case # Syndrome Dose [mg]/at onset Dose/time to remission
1
Bizarre visual hallucinations When ­ to 4.0/day ¯ to 3.2/day/1 day 

no further psychiatric symptoms

2
Visual hallucinations/ not bothersome 2.5/day after 16 months Dose unchanged / hallucination unchanged over 18 months
3
Memory loss/rage/insomnia irritability/depression 6/day after 10 months ¯ to 5.4/day led to improved mentation but unacceptable worsening of mobility. An effective dose without psychiatric effects was not established
4
Anxious/vivid hallucinations 0.5/day Stopped/cleared in 7 days 

Subsequently he tolerated 0.8 mg/day with rare visual hallucinations with full insight about them

5
Anxious/hallucinations / disorientation/frightening dreams 0.5/day/few days No dose change/clear in 2 

Later her dose was ­ to 2.0/day which she tolerated for 1 year without problems

6
Apathy/anorexia 3.6/day/8 months Resolved when dose ¯ to 3/day
 

They consider the psychiatric effects of pergolide to be similar to those reported with levodopa or bromocriptine. Hallucinations appeared in patients with no psychiatric history and rapidly subsided when the pergolide dose was reduced. One of the factors predictive of psychiatric side effects with levodopa is known to be rapid increases in dosage.

Mizuno and colleagues (1995), studied 314 patients on pergolide in combination with levodopa in a 2-4 year open trial. The maximum daily dose of pergolide was 2.25 mg, the mean daily maintenance pergolide dose was 1.25 mg +/- 0.58. They described three groups of patients; those on pergolide alone, the group on pergolide [first] with levodopa added, and the remainder on levodopa [first] with pergolide added. The reported incidence of psychiatric side effects during the open trial period was:

 
Pergolide Alone
Pergolide + levodopa
Levodopa + pergolide
Delusion
3 [8.8%]
3 [10.7%]
30 [9.6 %]
Hallucination
5 [14.7%]
6 [21.4%]
68 [21.7%]
Their report suggests that hallucinations and delusions can become a problem in long term treatment with pergolide. They speculated that the incidence of side effects might be greater when larger doses of pergolide (3-6 mg/day) are used in patients with late stages of Parkinsonís disease.

Serotonin syndrome [SS]

In June 1991 Sternbach published a review of SS in the American Journal of Psychiatry. Subsequently, discussions or reviews of SS have been published in the pharmacology (Nierenberg, 1993), neurology (Bodner, 1995), psychopharmacology (Lane, 1997), and emergency services literature (Brown, 1996). Recently a summary was added to one of the standard drug interaction references (Hansten, 1998).

Theoretically, any substance or combination of substances that has the effect of increasing serotonin neurotransmission can produce SS. SS usually occurs after a dose increase, overdose or drug interaction involving one or more serotonergic drugs. Onset is often within a few hours to twenty-four hours after a change in medication. SS may present as a mild, self limiting syndrome or with cognitive-behavioral changes (confusion, agitation) neuromuscular abnormalities (tremor, myoclonus, incoordination) and/or autonomic dysfunction (shivering, diarrhea, fever, diaphoresis, nausea and vomiting, and variable effects on blood pressure). There is no typical presentation of SS. Mild cases of SS can resolve within a few hours without specific treatment. However, in severe cases, death can occur within a few hours of presentation (Nierenberg, 1993; Bodner, 1995; Lane, 1997; Brown, 1996; Hansten, 1998).

Although cases of SS with MAOIís and various interacting drugs are well known, a case with iproniazid and a single dose of meperidine suggests that anyone could develop SS when given the "wrong" combination of serotonergic agents (Mitchell, 1955). Of particular importance is the fact that dextromethorphan, a common ingredient of OTC cold products, has been implicated in the development of SS (Harvey, 1995).

Isolated cases of SS in Parkinsonís disease have been described. Some believe that the myoclonus associated with l-dopa use is a form of mild SS. Sandyk (1986) described a 68 YOM, with a 7 year history of Parkinsonís, who had done well on Sinemet 25/250 twice daily for 2 years, was switched to bromocriptine maximum dose 60 mg/day and was stable for about 3 years. About 2 years prior to admission he gradually became depressed, immobile and rigid. Attempts to increase the bromocriptine produced no improvement. His bromocriptine dose was reduced to 20 mg/day, over a week, and Sinemet 25/250 was started and increased to three tablets daily over a week. On the 7th day he developed the following syndrome, which improved after methysergide was given:

Encephalopathic, with constant shivering of the entire body, severe action myoclonus involving both the trunk and limbs, gross resting and action tremor, hyperreflexia of the lower limbs and sustained patellar clonus. He appeared extremely distressed, was sweating profusely and developed diarrhea. His vital signs were: 180/100 mmHg; 110 bpm; 37.9C. Mills (1995) has recently summarized the signs and symptoms in 100 reported cases of SS and discussed current management options.

FOLLOW-UP:

Phone conference 4/29/99: The patient does acknowledge some less severe delusional thoughts about his body substances oozing out, but nothing like the episode in February. Recently started ropinirole, his Sinemet is now on PRN basis; no frightening hallucinations. However, the patient is stiffer than before. He is followed in the movement disorder clinic by an attending neurologist.

COMMENT:

The patientís history, clinical presentation, drug regiment (high dose pergolide), and his improvement after pergolide dose reduction are consistent with the well-established pattern of psychiatric adverse effects associated with dopamine agonists, including pergolide. His clinical presentation was inconsistent with the occurrence of a serotonin syndrome.


Dave Mace, R.Ph., Drug Information Specialist, prepared the article. Mace graduated from the University of Iowa College of Pharmacy in 1967. Since 1982 he has served as the Director of the Drug Information Center at BPVAMC, 10,000 Bay Pines Blvd., Bay Pines, FL 33744. His responsibilities include serving as a preceptor for drug information and Pharm.D. clerkship programs and responding to complex drug information requests from clinical staff.

EDITOR'S NOTE: From time to time, we publish articles contributed by IDIS subscribers. An article from Dave Mace, B.S.Pharm., is included in this issue. Dave Mace is from an institution that is a long-standing IDIS subscriber, utilizing the database on a regular basis. His consult illustrates IDIS database use contributing directly to patient care outcomes. The responsibility for errors is the author's alone. The consult does not necessarily represent hospital views and recommendations. We hope you find the information interesting and useful and welcome comments. If you are interested in sharing your experiences using the IDIS database, please contact donna-brus@uiowa.edu.

Donna Brus, Editor
 References:

1. Bodner, RA, et al. Serotonin syndrome. Neurology, 1995;45:219-223. (IDIS article number 342350 )
2. Brown TM, et al. Pathophysiology and management of the serotonin syndrome. Ann Pharmacotherapy 1996; 30:527-533. (IDIS article number 364938)
3. Cummings JL. Behavioral complications of drug treatment of Parkinsonís disease. J Am Geriatr Soc, 1991;39:708-716. (IDIS article number 284324)
4. Goetz CG, et al. Pharmacology of hallucinations induced by long-term drug therapy. Am J Psychiatry, 1982;139:494-497.
5. Hansten PD and Horn JD, editors. Hansten and Hornís Drug interactions analysis and management. Vancouver WA: Applied Therapeutics Inc. 1998 Oct. p. N123-N126.
6. Harvey AT, et al. Serotonin syndrome associated with paroxetine, an over-the-counter cold remedy, and vascular disease. Am J Emerg Med, 1995;13:605-606. (IDIS article number 353565)
7. Lane R et al. Selective serotonin reuptake inhibitor-induced serotonin syndrome: Review. J Clin Psychopharmacol, 1997;17:208-221. (IDIS article number 386544)
8. Lieberman A. Managing the neuropsychiatric symptoms of Parkinsonís disease. Neurology, 1998;50(suppl 6):S33-S38. (IDIS article number 408802)
9. Mills KC. Serotonin syndrome. Am Fam Physician, 1995;52:1475-1482. (IDIS article number 354648)
10. Mitchell RS, et al. Fatal toxic encephalitis occurring during iproziazid therapy in pulmonary tuberculosis. Ann Intern Med, 1955;42:417-424.
11. Mizuno Y, et al. Pergolide in the treatment of Parkinsonís disease. Neurology, 1995;45(suppl 3):S13-S21. (IDIS article number 347115)
12. Nierenberg DW, et al. The central nervous system serotonin syndrome. Clin Pharmacol Ther,1993;53:84-88. (IDIS article number 308978)
13. Sandyk R. L-Dopa induced ĎSerotonin Syndromeí in a parkinsonian patient on bromocriptine. J Clin Psychopharmacol, 1986;6:194-195. (IDIS article number 216265)
14. Serby M, et al. Mental disturbances during bromocriptine and lergotrile treatment of Parkinsonís disease. Am J Psychiatry, 1978;135:1227-1229. (IDIS article number 102311)
15. Stern Y, et al. Pergolide therapy for Parkinsonís disease: Neurobehavioral changes. Neurology, 1984;34:201-204. (IDIS article number 181341)
16. Sternback H. The serotonin syndrome. Am J Psychiatry; 1991;148:705-713. (IDIS article number 282914)
17. Turner TH, et al. Psychotic reactions during treatment of pituitary tumors with dopamine agonists. Br Med J, 1984;289:1101-1103. (IDIS article number 193101)


IDIS System/CD-ROM and Year 2000 Compliance

IDIS System/CD-ROM is Year 2000 compliant. The publication year is the only date field in the database and is currently in four-digit format. There is no code in the retrieval software which is affected by the system date. Please contact us if you need additional information.
 


KEY REFERENCES 

 

NEW DRUG SELECTED BIBLIOGRAPHY

This new drug selected bibliography provides a selection of key clinical studies and reviews of new drugs approved by the FDA from February through April 1999. IDIS SYSTEM/CD-ROM was searched to retrieve key articles relevant to the new drugs and their approved uses.

Amprenavir

Kaul DR, Cinti SK, Carver PL et al. HIV protease inhibitors: Advances in therapy and adverse reactions, including metabolic complications. Pharmacotherapy 1999;19:281-298. (IDIS Article Number 422546). A comprehensive review on the use of Protease inhibitors including amprenavir for treatment of HIV infection.

Denileukin Diftitox

LeMaistre CF, Saleh MN, Kuzel TM, et al. Phase I trial of a ligand fusion-protein (DAB389IL-2) in lymphomas expressing the receptor for interleukin-2. Blood 1998;91:399-405. (IDIS Article Number 399386). A phase I multicenter, open-label, dose-escalation trial was conducted to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of denileukin diftitox in 35 patients with relapsed cutaneous T-cell lymphoma.

Orlistat

Davidson MH, Hauptman J, DiGirolamo M et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized trial. JAMA 1999;281:235-242. (IDIS Article Number 417495). A multicenter, randomized, double blind, placebo-controlled, two-year study was conducted to evaluate the efficacy of orlistat therapy combined with dietary intervention in 892 obese patients.

 Sjostrom L, Rissanen A, Andersen T et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998;352:167-173. (IDIS Article Number 407969). Investigators enrolled 743 obese patients in a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and tolerability of orlistat (120 mg 3 times daily) in promoting weight loss and preventing weight regain over a two-year period.

Hollander PA, Elbein SC, Hirsch IB et al. Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care 1998;21:1288-1294. (IDIS Article Number 411429). A multicenter, randomized, double-blind, placebo controlled trial was conducted to assess the impact of orlistat therapy (120 mg 3 times daily) over a period of one year on weight loss, glycemic control, and serum lipid levels in 322 obese patients with type 2 diabetes on sulfonylurea medication.

 Ruth Calloway, R.Ph., M.S.
 

 
FDA DRUG/BIOLOGIC APPROVALS
 
Generic Name 

(FDA Therapeutic Classification) 

Trade Name

Sponsor 

(Approval Date)

Valid IDIS Drug Term 

Drug Number 

(IDIS Citations)*

Indication/Use Valid IDIS Disease Term 

Modified ICD-9-CM Number

Alitretinoin  

(1P)** 

Panretin

Ligand 

(Feb. 2)

ALITRETINOIN 

10120174 

(8 citations)

Topical treatment of cutaneous lesions of AIDS-related Kaposiís sarcoma Kaposiís Sarcoma 

176. 

Syn-Acq Immune Deficiency 

042.

Amprenavir 

(1P) 

Agenerase

Glaxo Wellcome, Inc. 

(April 15)

AMPRENAVIR 

8180847 

(7 citations)

For use in children age four and older and in adults in combination with other antiretrovirals for HIV infection Syn-Acq Immune Deficiency 

042. 

Infection, HIV, Asymptomatic 

V08.

Denileukin diftitox 

Ontak

Seragen, Inc. 

(Feb. 5)

DENILEUKIN DIFTITOX 

14000421 

(8 citations)

Treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor Neop, MGN-Lymph/Histio NEC 

202.

Orlistat 

(1P) 

Xenical

Roche Laboratories, Inc. 

(April 23)

ORLISTAT 

44100067 

(65 citations)

Treatment of obesity Obesity 

278.0

Sodium ferric gluconate complex 

(1P) 

Ferrlecit

Makoff R & D Labs (Schein will market) 

(Feb. 18)

FERRIC SODIUM GLUCONATE 

20040485 

(7 citations)

Treatment of iron deficiency anemia in patients undergoing chronic hemodialysis who are receiving supplemental erythropoetin therapy Anemia, Iron Deficiency 

280. 

Hemodialysis 

39.95

* Through May 1999 Update. Complete bibliographic citations will be provided upon request.
** (1P) New Molecular Entity given priority review by FDA
NEW VALID DRUG TERM
PHARMACOLOGICAL AGENTS 00100000

The new valid drug term PHARMACOLOGICAL AGENTS 00100000 has been added to the drug vocabulary beginning with the April 1999 update. Articles that contain general drug information for which specific drugs are not identified or are only used to illustrate a concept will be indexed with this term. Such articles would include general information on drug metabolism, general information on adverse drug reactions in special populations, and pharmacokinetic-pharmacodynamic modeling.

The following articles have been indexed with the drug term PHARMACOLOGICAL AGENTS and illustrate the use of this new drug term.

Shenfield G and Gross A. Thy cytochrome P450 system and adverse drug reactions. Adverse Drug React Bull 1999:739-742. (IDIS Article Number 423547)

Hall SD, Thummel KE, Watkins PB et al. Molecular and physical mechanisms of first-pass extraction. Drug Metab Dispos 1999;27:161-166. (IDIS Article Number 422656)

Verbeeck RK and Horsmans Y. Effect of hepatic insufficiency on pharmacokinetics and drug dosing. Pharm World Sci 1999;20:183-192. (IDIS Article Number 421571)

Brewer T and Colditz GA. Postmarketing surveillance and adverse drug reactions. Current perspectives and future needs. JAMA 1999;281:824-829. (IDIS Article Number 420369)

Volosov A and Bialer M. User of mean residence time to determine the magnitude of difference between rate constants and to calculate tmax in the bateman equation. Biopharm Drug Dispos 1999;20:3-9. (IDIS Article Number 420323)

 


MEETING THE CHALLENGES OF THE INFORMATION EXPLOSION

 
In this Information Age, we find ourselves surrounded by a wealth of information. The field of drug information has also experienced this information explosion.

The IDIS database, which has about 423,000 articles (as of May 1999), is growing at an accelerated pace. The projected number of articles to be indexed and added to the database in 1999 is 21,000, a 20 percent increase from 1995 when we added 17,5000 articles. The number of articles with abstracts to be included in the database has increased from 52 percent to 56 percent of total articles during this same period.

This increase in articles has not come about through a significant addition to the number of journals we index. Rather, IDIS indexers are finding more indexable articles per journal than they have in the past.

A wealth of information is only of value to you if you can access what is relevant when you need it. The IDIS mission it "to stimulate the effective use of drug information resources and promote better patient care through drug therapy."

At IDIS we're working harder, faster and smarter to keep up with the growing world of drug information. We want to help you make the information explosion work for you.

Barb Gericke, Jane Heaton
 

 
1999 EXHIBIT SCHEDULE
 Iowa Pharmacists Association Annual Meeting
Cedar Rapids, Iowa
June 11-13
Federation Internationale Pharmaceutique (FIP)
World Congress of Pharmacy and Pharmaceutical Sciences
Barcelona, Spain
September 5-10
American College Clinical Pharmacy (ACCP) Annual Meeting
Kansas City, Kansas
October 24-27
American Society of Health-System Pharmacists (ASHP)
Midyear Clinical Meeting
Orlando, Florida
December 5-9
 
 
STAFF PROFILE
 
Zinatara (Tina) Manji has lived in Iowa since 1972, when her family arrived as Ugandan refugees. With the completion of her M.S. and Pharm.D. degrees at the University of Iowa, she plans to pursue a professional career on the East Coast. Tina enjoys travel, music, exercise, and reading the New York Times. 

Zinataraís duties involve preparation of SBA documents for indexing and production. 

 
 
 
World of Drug Information is published quarterly (March, June, September, December) by the Division of Drug Information Service. 

Editor: Donna Brus 
Assistant Editor: Tracy Simenson 
Production/Design: Laura Kastens 
Photographer: David Luck 



 
IDIS 
Iowa Drug Information Service 
Telephone: 319-335-4800 
U.S. Toll-Free: 800-525-IDIS 
Fax: 319-335-4440 
E-mail: IDIS@uiowa.edu 
Web Site: http://www.uiowa.edu/~idis
IDIN 
Iowa Drug Information Network 
Telephone: 319-335-4199 
U.S. Toll-Free: 800-791-7055 
Fax: 319-335-4440 
E-mail: IDIN@uiowa.edu 
Web Site: http://idin.idis.uiowa.edu
Division of Drug Information Service
The University of Iowa, 100 Oakdale Campus N330 OH
Iowa City, IA 52242-5000 USA

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